Background: Isotretinoin for oral therapy in severe acne conglobata and acne nodulocystica represents a significant achievement; however, the drug exerts several mucocutaneous and systemic adverse effects, besides its teratogenic potency. Objective: The aim of this study was to investigate the plasma levels of isotretinoin and of 4-oxo-isotretinoin over long-term treatment of severe acne and to assess any correlation with the given dose, the clinical improvement and the occurrence of side effects. Methods: Forty-one patients with severe acne and acne-related disorders were studied under long-term oral intake of isotretinoin. Therapeutic effects and side effects were evaluated prior, during and at the end of therapy. The plasma levels of isotretinoin and of its major metabolite 4-oxoisotretinoin were measured by reversed-phase HPLC and were correlated with the administered oral dose and the number and frequency of side effects. Results: Dose-dependent plasma levels of isotretinoin and its metabolite were observed. At a mean dosage of 0.75–1.0 mg/kg/day, 404 ± 142 ng/ml were measured, whereas the plasma levels of 4-oxo-isotretinoin were 1–2 × higher. The plasma levels correlated well with the orally administered dose of isotretinoin and the observed mucocutaneous side effects. Conclusion: The study demonstrates that measuring of the plasma levels may be a helpful tool to monitor the individual therapeutic dose regimen in patients with severe acne in order to minimize undesired side effects and to control oral intake.

1.
Peck G, Olsen TG, Yocker FW, Strauss JS, Dowing DT, Pandya M, Butkus D, Arnaud-Battandier J: Prolonged remissions of cystic acne and conglobate acne with 13-cis-retinoic acid. N Engl J Med 1979;300:329–333.
2.
Goldstein JA, Socha-Szott A, Thomsen RJ, Pochi PE, Shalita AR, Strauss JS: Comparative effect of isotretinoin and etretinate on acne and sebaceous gland secretion. J Am Acad Dermatol 1982;6:760–765.
3.
Orfanos CE, Bauer E: Evidence for anti-inflammatory activities of oral synthetic retinoids: Experimental findings and clinical experience. Br J Dermatol 1983;109:55–60.
4.
Strauss JS, Stranieri AM: Changes in long-term sebum production from isotretinoin therapy. J Am Acad Dermatol 1982;6:751–755.
5.
Vane FM, Buggé CJL: Identification of 4-oxo-13-cis-retinoic acid as the major metabolite of 13-cis-retinoic acid in human blood. Drug Metab Dispos 1981;9:515–520.
6.
Allen JG, Bloxham DP: The pharmacology and pharmacokinetics of the retinoids. Pharm Ther 1989;40:1–27.
7.
Orme M, Back DJ, Shaw MA, Allen WL, Tjia J, Cunliffe WJ, Jones DH: Isotretinoin and contraception. Lancet 1984;29:752–753.
8.
Shalita AR: Lipid and teratogenic effects of retinoids. J Am Acad Dermatol 1988;19: 197–198.
9.
Bigby M, Stern RS: Adverse reactions to isotretinoin: A report from the Adverse Drug Reaction Reporting System. J Am Acad Dermatol 1988;18:543–552.
10.
Gollnick H, Ehlert R, Rinck G, Orfanos CE: Retinoids: An overview of pharmacokinetics and therapeutic value. Methods Enzymol 1990;190:291–304.
11.
Brazzell RK, Colburn WA: Pharmacokinetics of the retinoids isotretinoin and etretinate: A comparative review. J Am Acad Dermatol 1982;6:643–651.
12.
Gollnick H, Orfanos CE: Klinisch-therapeutischer Index und Dosimetrie der oralen Behandlung mit aromatischem Retinoid: ein Vergleich unterschiedlicher Dosierungen. Hautarzt 1983; 34:605–611.
13.
Buggé CJL, Rodriguez LC, Vane FM: Quantitation of isotretinoin or etretinate and their major metabolites in human blood by reversed-phase high performance liquid chromatography. J Pharm Biomed Anal 1985;3:269–281.
14.
Orfanos CE, Zouboulis ChC, Almond-Roesler B, Geilen CC: Current use and future potential role of retinoids in dermatology. Drugs 1997; 53:358–388.
15.
Brazzell RK, Vane FM, Ehmann CW, Colburn WA: Pharmacokinetics of isotretinoin during repetitive dosing to patients. Eur J Clin Pharmacol 1983;24:695–702.
16.
Cunliffe WJ, Layton A, Knaggs HE, Stubbings J, Taylor JP: Isotretinoin and acne: A long-term study; in Saurat J-H (ed): Retinoids: 10 Years On. Basel, Karger, 1991, pp 274–280.
17.
Rollmann O, Vahlquist A: Oral isotretinoin (13-cis-retinoic acid) therapy in severe acne: Drug and vitamin A concentrations in serum and skin. J Invest Dermatol 1986;86:384–389.
18.
Strauss JS, Rapini RP, Shalita AR, Konecky E, Pochi PE, Comite H, Exner JH: Isotretinoin therapy of acne: Results of a multicenter dose-response study. J Am Acad Dermatol 1984;10: 490–496.
19.
Orfanos CE: Retinoide: der neue Stand. Hautarzt 1989;40:123–129.
20.
Colburn WA, Gibson DM, Wiens RE, Hanigan JJ: Food increases the bioavailability of isotretinoin. J Clin Pharmacol 1983;23:534–539.
21.
Saurat JH: Side effects of systemic retinoids and their clinical management. J Am Acad Dermatol 1992;27:23–28.
22.
Almond-Roesler B, Orfanos CE: trans-Acitretin wird in Etretinat rückmetabolisiert: Bedeutung für die orale Retinoidtherapie. Hautarzt 1996;47:173–177.
23.
Barth JH, MacDonald-Hull SP, Mark J, Jones RG, Cunliffe WJ: Isotretinoin therapy for acne vulgaris: A re-evaluation of the need for measurements of plasma lipids and liver function tests. Br J Dermatol 1993;129:704–707.
24.
Gollnick H, Tsambaos D, Orfanos CE: Risk factors promote elevations of serum lipids in acne patients under oral 13-cis-retinoic acid (isotretinoin). Arch Dermatol Res 1981;271: 189–196.
25.
Vahlquist C, Olsson AG, Lindholm A, Vahlquist A: Effects of gemfibrozil (Lopid®) on hyperlipidemia in acitretin-treated patients: Results of a double-blind cross-over study. Acta Derm Venereol (Stockh) 1995;75:377–380.
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